The methods employed in this study were registered in PROSPERO (registration number: CRD42024562320), and strictly adhered to the PRISMA statement (Page et al., 2021).

We performed a comprehensive search across 6 databases, including PubMed, the Cochrane Library, Embase, the Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Databases (WF) and VIP, with no language restrictions, covering the 20-year period from 1 Jan 2004, to 1 June 2024. Two independent reviewers (DYT and FRL) conducted the search process. The search strategy integrated both Medical Subject Headings (MeSH) terms and free-text words. The language restriction was set to English and Chinese. The search terms included “acne vulgaris,” “acne,” and “Tanshinone capsule,” and related terms; the Chinese subject terms “Cuochuang” and “Danshentong” and related terms were used. The search strategies were adjusted according to the characteristics of different databases. Details of the search strategies are shown in Supplementary Materiale S4.

Studies meeting any of the following criteria were excluded: (1) studies focusing on other diseases accompanied by acneiform lesions, such as rosacea, SAPHO syndrome, polycystic ovary syndrome. (2) the treatment in control group or experiment group included unconventional therapy, such as acupuncture and moxibustion. (3) studies lacking mention of randomization (5) Studies lacking the specified outcome measures or reporting only AEs. (6) duplicate studies or those without full-text availability.

First, the primary literature retrieved from different databases was imported into the NoteExpress 3.8 software. After sequentially reading the titles, abstracts, and full texts, the final included studies were determined based on the inclusion and exclusion criteria. Second, two reviewers independently engaged in the screening of studies and extraction of data. Third, each included study was categorized, and Relevant data was extracted and recorded primarily including authors, publication years, sample sizes, gender ratios, intervention details, and outcome indicators. Fourth, the Cochrane Handbook (version 5.1.0) was used to evaluate the risk of bias according to the required items. Two independent reviewers (DYT and FRL) performed these tasks and if any discrepancies arose, they were resolved by a third researcher (LYW).

Meta-analysis was conducted using Review Manager (version 5.4). Continuous variables were expressed as mean difference (MD),while binary variables were expressed as risk ratio (RR), both with 95% confidence intervals (CIs). Heterogeneity was assessed using the I ² test. A fixed-effects model was adopted when I ² was <50%, indicating a low heterogeneity. Otherwise, a random-effects model was used. Subgroup analysis was conducted to investigate the potential influence of treatment duration and intervention methods for the experimental groups. Sensitivity analysis was conducted by excluding individual studies to assess the stability of the results. Publication bias was evaluated using Begg test and Egger test, facilitated by Stata SE 12.0 software. The quality of evidence for the outcome indicators was assessed using the GRADEpro system, which includes 5 downgrade factors and 3 upgrade factors.

Initially, we retrieved and identified 1,523 articles that met the study period criteria, and then 822 duplicate studies were removed. After screening the titles and abstracts, 573 articles were excluded. Following a detailed evaluation of the full texts, an additional 100 studies were excluded (reasons for exclusion are shown in Supplementary Table S2). Consequently, a total of 28 studies (Chen and Li, 2023; Ma, 2023; Gu et al., 2023; Zhang et al., 2022; Zou, 2022; Pei and Shang, 2022; Zhang et al., 2021; Luo and Liu, 2021; Cai et al., 2021; Song, 2020; Lan, 2019; Kang and Yang, 2019; Kang et al., 2019; Liu et al., 2018; Yang T. et al., 2018; Xia, 2018; Wu, 2018; Peng, 2017; Zhou et al., 2017; Yan and Dong, 2016; Chen et al., 2015; Qin et al., 2015; He et al., 2015; Jiang and Sheng, 2015; Zhao and Yan, 2015; Lin et al., 2009; Chen and Liu, 2007; Cong et al., 2019) were included in the analysis. Details of the screening process are shown in Figure 1.

Regarding selection bias, fifteen studies (Liu and Ma, 2023; Chen and Li, 2023; Ma, 2023; Pei and Shang, 2022; Zhang et al., 2021; Luo and Liu, 2021; Song, 2020; Lan, 2019; Yang T. et al., 2018; Wu, 2018; Peng, 2017; Zhou et al., 2017; Chen et al., 2015; Qin et al., 2015; He et al., 2015) used the random number table method and 1 study (Gu et al., 2023) used random drawing method, which was rated as low. One study (Zhang et al., 2022) was considered high risk due to random grouping based on the order of patient visits. The remaining 11 studies (Zou, 2022; Cai et al., 2021; Kang and Yang, 2019; Kang et al., 2019; Liu et al., 2018; Xia, 2018; Yan and Dong, 2016; Jiang and Sheng, 2015; Zhao and Yan, 2015; Lin et al., 2009; Chen and Liu, 2007) did not report the method for generating random sequences and were rated as unclear risk. None of the studies explained the randomization method in detail, which was considered to be an unclear risk of bias. Due to the significant differences in the formulation of treatments between the treatment and control groups, performance bias was rated as high. For detection bias, one study (He et al., 2015) was considered low risk as outcome data collection and assessment was conducted under blinding. All studies had no patients fell off, all studies reported test indicators as planned, and there was no selective reporting of research results. It is unclear whether there were other examples of bias. The Risk of bias graph is shown in Figure 2.

Regarding the relapse rate, the Begg test results were: z = 2.47 (continuity corrected), Pr > |z| = 0.013 (continuity corrected), thus we conducted trim-and-fill test analysis, the results showed that Q = 1.961, p = 1.000, IOR = 0.416, 95%CI: 0.086 to 0.746; and the Egger test results were: t = −1.72, P > |t| = 0.108. These results indicated the absence of statistical significance in terms of publication bias (Figure 13).

The quality of evidence was assessed using the GRADEpro. The quality of evidence ranged from very low to moderate. The primary reasons for downgrading were inconsistency (high heterogeneity and uneven gender ratio), imprecision (small sample size) and risk of bias (unclear blinding). This is illustrated in Figure 14.

This study evaluated the efficacy and safety of Tanshinone capsules in treating acne vulgaris. A total of 28 trials involving 2,969 patients with acne vulgaris were included. The meta-analysis results demonstrated that Tanshinone capsules had a significant impact on reducing acne recurrence rates, lowering GAGS scores for skin lesions, and decreasing sebum secretion rates, suggesting that Tanshinone capsules can offer a significant and long-lasting improvement in acne lesions and associated symptoms. Furthermore, analysis of inflammatory factor levels indicated that Tanshinone capsules significantly reduced TNF-α, IL-4, IL-6, and IL-8 levels. Suggesting that Tanshinone capsules can effectively alleviate inflammation and prevent the progression of inflammatory conditions. Given the close relationship between acne onset and patients’ hormone levels, we also conducted a meta-analysis of hormone levels, the results showed that Tanshinone capsules effectively lowered testosterone levels, contributing to acne treatment. The effects of Tanshinone capsules on acne are attributable to multi-factors. However, although previous studies have reported that Tanshinone exhibits both anti-androgenic effects and estrogen-like activity, the meta-analysis did not find any significant differences in LH, FSH, or E₂ levels. In terms of safety, none of the included studies reported severe adverse events, and the meta-analysis results showed that Tanshinone capsules were associated with fewer adverse events compared to control groups. In summary, Tanshinone capsules effectively improve acne lesions, reduce excessive sebum secretion, regulate inflammatory markers and testosterone levels, and demonstrate long-lasting efficacy with a favorable safety profile.

Tan ⅡA and CPT, the main active ingredients in Tanshinone capsules, show antibacterial activity against acne-related pathogenic microorganisms in vitro studies (Zhu et al., 2022; Li and Zhou, 2018). C. acnes activates the NF-κB pathway through TLR2, resulting in elevated levels of IL-1β, IL-6,IL-8, and TNF-α (Cong et al., 2019). Tanshinone can reduce the levels of IL-8, IL-6, IL-1β, and TNF-α in acne model rats, as profiled by lipidomics, with the mechanism possibly related to sphingolipid and glycerophospholipid metabolism pathways (Chen et al., 2021). Tan ⅡA treatment inhibits the TLR2/NF-κB pathway and suppress the expression of inflammatory cytokines IL-1β, IL-8, and TNF-α (Li and Zhou, 2018). CPT contributes to reducing the levels of inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α in acne model rats. This effect may be related to downregulating the expression of keratin, inhibiting glycolysis/gluconeogenesis and histidine metabolism, modulating lipid metabolism and altering sebum production, as well as downregulating the IL-17 signaling pathway, based on proteomics and metabolomics (Zhu et al., 2021). CPT helps restore the structure of skin microbiota, improve lipid metabolite composition and concentration, and negatively regulate the glycolysis pathway, thereby inhibiting excessive keratinocyte proliferation and reducing acne inflammation. (Zhu et al., 2022). Tan ⅡA and CPT can inhibit sebocyte proliferation and lipid synthesis, as well as downregulate AR expression (Ju et al., 2005). IL-4 expression is increased in acne hypertrophic scars, which is significantly importance for the prognosis of acne vulgaris (Yang J. H. et al., 2018). However, due to the unclear mechanism of Tanshinone’s effect on IL-4 during the course of acne, these results should be interpreted with caution. Furthermore, other studies have found that Tanshinones exhibit both anti-androgenic and estrogen-like activity (Zhang et al., 2019; Siddique et al., 2012).

Overall, Tanshinones can intervene in the growth of pathogenic microorganisms, lower inflammatory cytokine levels to alleviate inflammatory responses, suppress sebaceous gland hyperplasia and excessive lipid secretion, and regulate hormone levels, thereby treating acne.

We assessed the impact of course of treatment and intervention methods in the experimental groups on the recurrence rate and levels of inflammatory factors (excluding IL-4), which are relevant to clinical practice. We found that in different treatment duration subgroups, Tanshinone capsules consistently reduced recurrence rates and TNF-α levels. This effect was also observed when Tanshinone capsules were used as a monotherapy or as an adjunctive therapy in combination treatments. Notably, results of the subgroup analyses were not entirely consistent. For IL-6 and IL-8 levels, Tanshinone capsules used as monotherapy were less effective than conventional treatments. Additionally, subgroup analysis indicated that when the treatment duration was 6 weeks or less, there was no significant difference between the treatment and control groups in IL-6 and IL-8 levels. We speculate that these discrepancies may be due to the limited number of included studies, as these subgroups typically consist of only one or two studies. Therefore, these findings should be interpreted with caution.

The sensitivity analysis showed that most results were stable. However, after excluding a single study, we observed instances where the outcomes for IL-6, IL-8, T, FSH, and sebum secretion rate exceeded the original 95% confidence interval, lost statistical significance, or exhibited increased heterogeneity. These findings indicate potential result instability, which should be interpreted with caution.

Some limitations of this study need to be addressed. First, since all the included studies were conducted in China, the generalizability of the results to other ethnicities may be limited. Further research is needed to validate these findings across different ethnic groups. Second, the included studies often lack a randomized controlled trial framework and provide insufficient details on patient stratification criteria, leading to an increased risk of bias that reduces the credibility of the findings. Therefore, the conclusions should be interpreted with caution. Third, since the mechanism of Tanshinone’s effect on inflammatory cytokines in acne has not been fully elucidated, the related results should be interpreted with caution. Fourth, the maximum treatment duration was 3 months (only 1 study). Due to the limited number of studies and follow-up data, the long-term clinical benefits and potential risks associated with extended treatment durations remain unclear. Finally, due to the varying criteria used to evaluate adverse events and interventions across studies, the results regarding AEs should be interpreted with caution.

The findings of our study indicate that Tanshinone capsules have great potential for acne treatment. This medication could be considered as a complementary medicine and deserves further exploration. In terms of future clinical study designs, large-sample, multicenter, long-term RCTs should be conducted, strictly adhering to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. At the same time, the quality could be improved by standardizing study protocols, unifying diagnostic criteria, enhancing randomization, allocation concealment, and blinding, as well as appropriately calculating sample sizes. In addition, it is essential to implement detailed long-term toxicity monitoring, create standardized patient follow-up protocols, select objective and scientific outcome indicators, and evaluate the impact on acne-related quality of life.

Furthermore, conducting comprehensive molecular and experimental pharmacological analysis, identifying potential biomarkers for predicting treatment response, and investigating the molecular mechanisms of Tan ⅡA and CPT in relation to their respective targets will enhance our understanding of the molecular characterization of Tanshinone. Simultaneously, applying advanced imaging and molecular tracking techniques, developing computational models to predict treatment response, and validating molecular mechanisms in clinical research will provide better guidance for clinical practice.